Impact of Gonadotrophin Dose Used on Ovarian Stimulation for IVF on Embryo Ploidy Status

Impact of Gonadotrophin Dose Used on Ovarian Stimulation for IVF on Embryo Ploidy Status | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of Gonadotrophin Dose Used on Ovarian Stimulation for IVF on Embryo Ploidy Status Alessandro Schuffner, Gabriela Schuffner, Camila Dutra De Souza Francisquini, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4797800/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Does the amount of gonadotrophin used during an IVF cycle affect the the number of euploid embryos by patients of different ages? Methods A descriptive, retrospective, observational study with 245 patients divided in two experimental groups considering the total gonadotropin dose used (≤ 3000 IU n = 150 or > 3000 IU n = 45). Results Patients from group ≤ 3000 IU had a shorter stimulation period, higher number of follicles, oocytes and MII retrieved, zygotes, number of blastocysts and euploid blastocysts. Regarding the kind of protocol, patients in rFSH-only group were younger, with more follicles, total and MII retrieved oocytes, zygotes, number of blastocysts and euploid blastocysts. When evaluating infertility diagnosis, the number of follicles, total and MII retrieved oocytes and zygotes were greater in the male factor group and unexplained factor compared to female plus male and mainly with female factor group. Moreover, the number of euploid blastocysts was greater in the unexplained factor group, and the female plus male group showed the lowest euploidy. A positive correlation was found between IVF outcomes and euploidy. A negative correlation was observed between embryo euploidy and maternal age and gonadotropin dose. Conclusions Lower doses of gonadotropin are more likely to produce more euploid blastocysts when comparing to higher dose group. The use of rFSH is related to younger patients and more euploid embryos. When female factor is present there was lower euploidy. It was also observed a positive correlation between embryo production and euploidy. ovulation induction aneuploidy in vitro fertilization preimplantation embryo What does this study adds to the clinical work Lower doses of gonadotropin are more likely to produce more embryos and more euploid blastocysts and the higher the dose of gonadotropin, the lower the production of euploid embryos. INTRODUCTION Assisted reproductive technologies (ART) is often the primary choice to treat human infertility. However, ART cannot fully compensate for female age-dependent loss of oocyte quality and quantity due to the fact that the success rates of these techniques also decrease with age [1]. In addition, hormonal hyperstimulation protocols, which include the use of gonadotropin to induce multiple ovulations are known to create a hostile endometrial environment [2]. In animal models studies it was observed that superovulation accelerate nuclear maturation and affect chromosome during prometaphase and metaphase, thus causing a higher risk of aneuploidies [3–5]. Researchers have investigated whether ovary hyperstimulation increases aneuploidy rate in women undergoing ART. It was suggested that stimulation with high-dose exogenous gonadotropins (225 IU recombinant FSH; rec-FSH) might lead to higher aneuploidy rates compared to mild (150 IU rec-FSH) stimulation [6]. A study published in 2012 showed no association between the number of embryos generated and aneuploidy rates [7]. Sekhon et al. [8] reported that exogenous gonadotropins did not significantly modify the aneuploidy rates in cases with up to 12 days of ovarian stimulation. In the same year, Barash and coworkers [9] showed that euploidy rates within the same age group were not statistically different regardless of the total dosage of gonadotropins (> 5000 IU or < 3000 IU). A retrospective study also showed higher aneuploidy rates in women undergoing stimulation with higher gonadotropin (≥ 200 IU) dosages [10]. Moreover, Munné et al. [11] demonstrated a significant difference in euploidy rates, ranging from 39.5 to 82.5%, among young oocyte donors. Therefore, determining the effect of exogenous gonadotropins on embryo ploidy in women undergoing ovarian stimulation is critical for the selection of the best stimulation protocols [12]. Studies exploring the relationship ovarian stimulation using gonadotropin and embryo euploidy have yielded inconclusive results, and some degree of controversy remains. Given the conflicting reports and lack of guidance regarding gonadotropin dosing, our goal was to evaluate de total amount of gonadotropin used during an IVF cycle and the number of euploid embryos produced after blastomere biopsy by patients of different ages. METHODS Experimental design and localization An observational, descriptive, and retrospective study was performed between February 2012 and December 2019 in an IVF Clinic at Curitiba, Paraná, Brazil. Participants The electronic registration of 1500 women that underwent IFV treatment with ovarian stimulations and preimplantation genetic testing for aneuploidies (PGT-A) between February 2012 and December 2019 were analyzed. Exclusion criteria were patients with low ovarian reserve, ovarian surgery, use of surgically retrieved semen for IVF, use of GnRH agonist for pituitary suppression and absence of PGT-A result. After exclusion criteria, the remaining 245 patients were divided in two experimental groups considering the total gonadotropin dose used during IVF treatment (Group ≤ 3000 IU n = 150; or Group > 3000 IU n = 95). After, for more statistical analysis, they were divided in five groups according kind of gonadotropin protocol (hMG-only n = 66; rFSH-only n = 90; rFSH + hMG n = 58; rFSH + rLH n = 22 or uFSH n = 9). Moreover, patients were divided in four groups considering infertility diagnosis (female n = 163; male and female n = 23; male n = 28 or Unexplained n = 31). The following data were collected: maternal age, infertility factors, gonadotropin dosage, the average ovarian stimulation period, the kind of gonadotropin, number of follicles, oocytes retrieved and metaphase II (MII), zygotes, blastocysts, number and rate of euploid embryos. Ovarian stimulation protocols All patients underwent controlled ovarian stimulation protocols according to the patient´s baseline characteristics and previous medical history. GnRH antagonist was used for pituitary suppression. Recombinant follicle stimulating hormone (rFSH) alone or in combination with human menopausal gonadotropin (hMG) or recombinant luteinizing hormone (rLH), hMG alone or urinary FSH (uFSH) alone were used as options of exogenous gonadotropin. Human chorionic gonadotropin (hCG) was used for triggering ovulation. Oocyte retrieval Approximately 35 hours after the hCG injection, the oocyte retrieval was performed under sedation. After retrieval, oocytes were incubated in culture medium CSCM-C (Irvine Scientific® Santa Ana, USA) covered with mineral oil (Oil for Embryo Culture, Irvine Scientific® Santa Ana, USA) at 37ºC and 6% CO 2 for 4 hours. Intracitoplasmic sperm injection (ICSI) ICSI was performed according to Palermo et al [13]. For ICSI, oocytes were placed individually in 3 µL droplets of buffered medium HTF (Irvine Scientific®, Santa Ana, USA). Sperm were placed in a central 5 µL droplet of polyvinylpyrrolidone solution (PVP, Irvine Scientific, Santa Ana, USA) in a 50X9 mm glass culture dish covered with warm mineral oil (Oil for Embryo Culture, Irvine Scientific® Santa Ana, USA). Assessment of fertilization and embryo quality Embryos were placed in a 50-µL drop of culture medium CSCM-C (Irvine Scientific® Santa Ana, USA) supplemented with 10% protein supplement, and were covered with paraffin oil in a humidified atmosphere under 7.5% CO 2 at 37ºC for 5 days. Fertilization was assessed 18 hours after ICSI, and normal fertilization (zygote) was declared when two clearly distinct pronuclei were present. Blastocyst quality was evaluated under an inverted microscope [14]. Biopsy and embryo cryopreservation For blastocyst biopsy, the embryos underwent assisted hatching with zona pellucida laser pulsing (OCTAX Laser Shot™; MTG Medical Technology, Germany) on day 3 of development. Only good-quality blastocysts were biopsied on day 5, in a 20-µL drop of buffered medium with 10% protein supplement and covered with paraffin oil. The hatching of the zona pellucida and trophectoderm was disposed at the 3 o’clock position, and gentle suction was applied to the blastocyst via a holding pipette (Humagen, Charlottesville, VA). A biopsy pipette (Humagen, Charlottesville, VA) was used to gently aspirate the trophectoderm into the bore of the needle. Laser pulses were used to "cut" the trophectoderm. After biopsy, embryos were vitrified. Both vitrification and the warming procedures were performed using the Frozen/Thawing Kit (Ingamed®, Londrina, Brazil). Embryo diagnosis The diagnosis was performed by NGS in an associated genetic laboratory, according to its established methodology. Data analysis Normal distribution was evaluated by Shapiro-Wilk test. Since all dependent variables did not show normal distribution, the Kruskal-Wallis and Dunn´s post hoc non-parametric tests were used. Spearman rank correlation coefficient was used for the correlation test. Data were evaluated using the MedCalc Software, version 20.006. A P value < 0.05 was considered statistically significant. RESULTS There was no interaction between the independent variables (gonadotropin dosage, kind of gonadotropin and infertility diagnosis) for all measured dependent variables, so their effects were tested individually. When evaluating both groups regarding gonadotropin dosage (Table 1 ) it was observed that the average maternal age was not different between the groups (p = 0.47). The median age of group ≤ 3000 IU was 37.54 (± 4.16) years old, while in the group > 3000 IU was 38.08 (± 3.57) years old. Table 1 – In vitro fertilization outcomes (ovarian stimulation period. number of follicles. number of oocytes and mature oocytes retrieved (MII). number of zygotes. blastocysts produced. number and rate of euploid embryos) and maternal age (years) according to gonadotropin dosage group (IU). Data presented as Mean ± SD. Gonadotropin Dosage Groups (n) ≤ 3000 IU (150) > 3000 IU (95) Maternal age (y) 37.54 ± 4.16 38.08 ± 3.57 Ovarian stimulation period 9.46 ± 1.72 a 11.80 ± 2.07 b Number of follicles 11.68 ± 7.18 a 9.13 ± 5.48 b Oocytes retrieved 10.81 ± 7.06 a 8.15 ± 5.80 b MII oocytes 8.43 ± 5.34 a 6.71 ± 4.75 b Zygotes 6.00 ± 4.15 a 4.27 ± 3.14 b Blastocyst 3.26 ± 2.40 a 2.14 ± 1.69 b Euploid embryo 1.12 ± 1.29 a 0.74 ± 0.95 b Euploid embryo rate 31.82 ± 33.42 32.17 ± 38.90 Different superscript letters in each line represent significant differences (P 3000 IU gonadotropin (P < 0.000001). Despite shorter stimulation period, patients from group ≤ 3000 IU produced higher number of follicles (p = 0.001963), oocytes retrieved (p = 0.000698), MII retrieved (p = 0.006211), zygotes (p = 0.000416), number of blastocysts (p = 0.000019) and euploid blastocysts (p = 0.03). On the other hand, the groups were equal regarding euploid embryo rate. When evaluating the kind of gonadotropin protocol, the sample was divided in five groups (hMG-only, rFSH-only, hMG plus rFSH, rFSH plus rLH or uFSH). (Table 2 ). The average maternal age was lower in the rFSH-only group and uFSH group than hMG plus rFSH group (p = 0.004607). Table 2 – In vitro fertilization outcomes (ovarian stimulation period. number of follicles. number of oocytes and mature oocytes retrieved (MII). number of zygotes. blastocysts produced. number and rate of euploid embryos) and maternal age (years) according to kind of gonadotropin protocol. Data presented as Mean ± SD. Kind of gonadotropin protocol (n) hMG-only (66) rFSH-only (90) rFSH + hMG (58) rFSH + rLH (22) uFSH (9) Maternal age (y) 38.33 ab ± 3.52 36.61 a ± 4.23 38.84 b ± 3.50 38.45 ab ± 3.98 36.22 a ± 3.86 Ovarian stimulation period 10.34 ± 2.40 10.23 ± 1.78 10.69 ± 2.46 9.72 ± 2.27 11.33 ± 1.93 Number of follicles 9.39 a ± 5.31 13.52 b ± 7.03 8.26 a ± 4.36 10.18 a ± 10.2 9.00 a ± 4.84 Oocytes retrieved 8.65 a ± 5.74 12.55 b ± 7.25 7.53 a ± 4.67 8.54 a ± 8.60 7.89 a ± 5.57 MII oocytes 7.03 a ± 4.70 10.22 b ± 5.77 5.89 a ± 3.66 5.27 a ± 3.43 6.78 a ± 5.11 Zygotes 4.72 a ± 3.65 6.98 b ± 4.29 4.07 a ± 2.70 3.86 a ± 2.91 4.89 a ± 4.48 Blastocyst 2.37 a ± 1.66 3.76 b ± 2.74 2.14 a ± 1.62 2.47 ab ± 1.51 2.55 ab ± 1.88 Euploid embryo 0.75 a ± 1.03 1.38 b ± 1.38 0.65 a ± 0.85 0.90 ab ± 0.92 0.89 ab ± 1.69 Euploid embryo rate 26.31 ± 31.31 34.42 ± 31.74 29.68 ± 39.59 49.24 ± 46.42 21.11 ± 35.83 Different superscript letters in each line represent significant differences (P < 0.05). Regardless of the kind of gonadotropin used, the average ovarian stimulation period was statistically similar. The number of follicles was greater in the group rFSH-only when compared with the number of follicles produced by patients with other gonadotropin protocols (p = 0.000002). Also, the number of retrieved oocytes (p = 0.000012), MII oocytes (p = 0.000001) and zygotes (p = 0.000001) were higher for women of rFSH-only gonadotropin protocol compared to other four gonadotropin protocol. Number of blastocysts (p = 0.000147) and euploid embryos (p = 0.003974) were greater in the rFSH-only group than hMG-only and hMG plus rFSH group. On the other hand, the groups were equal regarding euploid embryo rate. The infertility diagnosis was also evaluated, and the sample was divided in four groups according the diagnosis as female, female plus male, male and unexplained (Table 3 ). The maternal age and ovarian stimulation period were similar among the groups. The number of follicles (p = 0.000035), oocytes retrieved (p = 0.000052), MII oocytes (p = 0.002277) and zygotes (p = 0.006993) were greater in the male factor group and unexplained factor compared to female plus male and mainly with female factor group. Independently of the infertility factor, number of blastocysts was similar among the groups. However, the number of euploid blastocysts was greater in the unexplained factor group (p = 0.020338), and the female plus male group showed the lowest euploidy. Table 3 – In vitro fertilization outcomes (ovarian stimulation period. number of follicles. number of oocytes and mature oocytes retrieved (MII). number of zygotes. blastocysts produced. number and rate of euploid embryos) and maternal age (years) according to infertility diagnosis. Data presented as Mean ± SD. Female (163) Male and female (23) Male (28) Unexplained (31) Maternal age (y) 38.01 ± 3.83 36.65 ± 5.34 36.35 ± 4.34 38.48 ± 2.43 Ovarian stimulation period 10.49 ± 2.18 9.52 ± 1.41 10.68 ± 2.00 10.06 ± 2.69 Number of follicles 9.64 a ± 6.32 10.65 ab ± 4.95 14.96 b ± 7.15 12.45 ab ± 7.53 Oocytes retrieved 8.81 a ± 6.60 9.13 ab ± 4.16 14.39 b ± 7.74 11.19 ab ± 6.11 MII oocytes 7.27 a ± 5.52 7.17 ab ± 3.57 9.85 b ± 4.22 8.90 ab ± 4.65 Zygotes 5.00 a ± 3.96 4.52 a ± 2.59 6.93 b ± 3.83 6.19 ab ± 3.90 Blastocyst 2.67 ± 2.06 2.65 ± 2.16 3.39 ± 2.92 3.29 ± 2.31 Euploid embryo 0.92 ab ± 1.17 0.56 a ± 0.89 1.21 ab ± 1.16 1.38 b ± 1.36 Euploid embryo rate 31.85 ab ± 36.95 15.72 a ± 26.37 39.96 b ± 33.75 37.68 ab ± 32.69 Different superscript letters in each line represent significant differences (P < 0.05). The correlation rate among maternal age, gonadotropin dosage, ovarian stimulation period, number of follicles, retrieved oocytes, MII occytes, zygotes, blastocyst production and euploid embryos is shown in Table 4 . Table 4 – Correlations (r) and significance levels (P) among the measured variables. Maternal age (y) Ovarian stimulation period Gonadotropin Dosage (IU) Number of follicles Oocytes retrieved MII oocytes Zygotes Blastocyst Euploid embryo Euploid embryo rate Maternal age (y) -0.095 (p = 0.1369) 0.062 (p = 0.3352) -0.418 (p < 0.0001) -0.387 (p < 0.0001) -0.381 (p < 0.0001) -0.342 (p < 0.0001) -0.367 (p < 0.0001) -0.430 (p < 0.0001) -0.357 (p < 0.0001) Ovarian stimulation -0.095 (p = 0.1369) 0.568 (p < 0.0001) 0.042 (p = 0.5119) -0.006 (p = 0.9285) 0.019 (p = 0.7689) -0.018 (p = 0.7754) -0.019 (p = 0.7619) 0.030 (p = 0.6414) 0.040 (p = 0.5302) Gonadotropin Dosage (IU) 0.062 (p = 0.3352) 0.568 (p < 0.0001) -0.169 (p = 0.0079) -0.200 (p = 0.0017) -0.163 (p = 0.0106) -0.195 (p = 0.0022) -0.236 (p = 0.0002) -0.133 (p = 0.0379) -0.043 (p = 0.5063) Number of follicles -0.418 (p < 0.0001) 0.042 (p = 0.5119) -0.169 (p = 0.0079) 0.942 (p < 0.0001) 0.904 (p < 0.0001) 0.819 (p < 0.0001) 0.600 (p < 0.0001) 0.442 (p < 0.0001) 0.214 (p = 0.0007) Oocytes retrieved -0.387 (p < 0.0001) -0.006 (p = 0.9285) -0.200 (p = 0.0017) 0.942 (p < 0.0001) 0.935 (p < 0.0001) 0.842 (p < 0.0001) 0.632 (p < 0.0001) 0.449 (p < 0.0001) 0.205 (p = 0.0013) MII oocytes -0.381 (p < 0.0001) 0.019 (p = 0.7689) -0.163 (p = 0.0106) 0.904 (p < 0.0001) 0.935 (p < 0.0001) 0.872 (p < 0.0001) 0.642 (p < 0.0001) 0.458 (p < 0.0001) 0.208 (p = 0.0011) Zygotes -0.342 (p < 0.0001) -0.018 (p = 0.7754) -0.195 (p = 0.0022) 0.819 (p < 0.0001) 0.842 (p < 0.0001) 0.872 (p < 0.0001) 0.726 (p < 0.0001) 0.504 (p < 0.0001) 0.228 (p = 0.0003) Blastocyst -0.367 (p < 0.0001) -0.019 (p = 0.7619) -0.236 (p = 0.0002) 0.600 (p < 0.0001) 0.632 (p < 0.0001) 0.642 (p < 0.0001) 0.726 (p < 0.0001) 0.624 (p < 0.0001) 0.277 (p < 0.0001) Euploid embryo -0.430 (p < 0.0001) 0.030 (p = 0.6414) -0.133 (p = 0.0379) 0.442 (p < 0.0001) 0.449 (p < 0.0001) 0.458 (p < 0.0001) 0.504 (p < 0.0001) 0.624 (p < 0.0001) 0.864 (p < 0.0001) Euploid embryo rate -0.357 (p < 0.0001) 0.040 (p = 0.5302) -0.043 (p = 0.5063) 0.214 (p = 0.0007) 0.205 (p = 0.0013) 0.208 (p = 0.0011) 0.228 (p = 0.0003) 0.277 (p < 0.0001) 0.864 (p < 0.0001) A negative correlation was found between maternal age and number of follicles, oocytes retrieved, MII retrieved, zygotes, blastocysts and euploid blastocysts (p < 0.0001). Maternal age did not correlated with gonadotropin dosage (p = 0.3352) or ovarian stimulation period (p = 0.1369). As expected, there was a positive correlation between period of ovary stimulation and total gonadotropin dose (p < 0.0001). However, the gonadotropin dose is negatively correlated to number of follicles (p = 0.0079), oocytes retrieved (p = 0.0017), MII retrieved (p = 0.0106), zygotes (p = 0.0022), blastocyst production (p = 0.0002) and euploid embryos (p = 0.0379). Euploid embryos were negatively correlated to maternal age (p < 0.0001) and gonadotropin dose (p = 0.0379). Conversely, a positive correlation was found among euploidy and number of follicles, oocytes retrieved, MII retrieved, number of zygotes and blastocysts and euploidy rate (p < 0.0001). DISCUSSION Several studies have revealed that over half of human preimplantation embryos produced by IVF treatment have chromosomal abnormalities [6, 15–17]. There are several factors in the IVF process that may influence ploidy status, including maternal age, gonadotropin stimulation, oocyte trigger, embryo culture conditions and even iatrogenic origin [9, 11, 18]. Yet, ovarian stimulation of suboptimal follicles containing poorer quality oocytes that would have otherwise been naturally selected to undergo atresia, has been hypothesized to increase oocyte aneuploidy [8]. The reported results here demonstrate that when comparing total gonadotropin doses or infertility factors, maternal age was not significant different. Although there was no significant difference in maternal age between the gonadotropin dosage groups, women with > 35 years of age usually experience a gradual loss of oocyte quality and quantity [12, 19]. Nevertheless, maternal age was positively related to the kind of gonadotropin used, since the oldest women were at hMG plus rFSH group, while the newest women were at rFSH-only group. Still, we found a negative correlation between IVF outcomes (number of follicles, oocytes and mature oocytes retrieved, zygotes, embryo production and euploidy) and maternal age. According to Alfarawati and co-workers [15] there is a strong association between maternal age and aneuploidy, increasing from 51% in embryos of patients aged 31–37 years to 60.7% in the embryos of women aged 38–47 years. Therefore, even with the exclusion of low ovarian reserve in the sample, it is possible that some patients included in the present study had at least some degree of decreased ovarian reserve (also called poor responder patients). Ovarian reserve determines the capacity of the ovary to produce oocytes that are capable of fertilization. Age is an important factor for ovarian reserve quality and quantity determination [20, 21] . The main goal of controlled ovarian stimulation with exogenous gonadotropins is to maximize the number of oocytes retrieved. Traditionally GnRH agonists have been used as a long protocol of ovarian stimulation [8, 22]. On the other hand, GnRH antagonists which prevent a premature LH surge were introduced as an alternative to the GnRH agonists allowing a shorter duration of treatment. The longer regimen of ovarian stimulation is associated with higher gonadotrophin consumption than shorter protocols. Yet, since the GnRH antagonist regimen (shorter protocol) avoids severe suppression of endogenous gonadotropins concentrations at the stage of follicular recruitment, this may be an advantage for older patients [20, 23]. All of the patients at this study underwent to GnRH antagonist protocol. Anyhow, the results showed here agree with published literature. The group that received lower dose of total gonadotropin (≤ 3000 IU) showed shorter period of ovary stimulation when compared to patients that received higher gonadotropin doses. Reports on the effects of high versus low gonadotropin stimulation on IVF outcomes present conflicting data [24, 25]. A report published by Wu and co-workers [26] showed that women with advanced maternal age (≥ 35 years of age) had no difference in the rate of blastocyst aneuploidy among different gonadotropins dose groups ( 3000 IU, 59.8%; P = 0.86). In contrast, some studies suggested that high gonadotropin doses might be associated with meiotic divisions errors [6, 17]. It could be speculated that high doses may be associated with the malfunction of intracellular reparation mechanisms and/or achromatic mitosis spindle assembly [27, 28]. Several studies have suggested that a high response to ovarian stimulation might be embryotoxic and/or increase oocyte aneuploidy rates by enhancing abnormal segregation of chromosomes during meiosis [3–5, 29, 30]. Barash et al. [9] observed that the proportion of good quality embryos decreased from 48.92–38.3%, while total dosage increased from under 3000 IU to over 5000 IU. Our results support findings which reported that lower dose of gonadotropin showed increased embryo yield. It was also observed that gonadotropin dose is inversely correlated to all IVF outcomes, including number of euploidy, but not euploidy rate. The number of oocytes retrieved is associated with the dose of gonadotrophin, but this can vary between individual women [31]. However, higher doses of gonadotrophins cannot compensate for the absence of follicles in the ovary [32], therefore increased doses of gonadotrophins are likely to be cost-effective only when there is adequate ovarian reserve [22]. This study supports that high doses of gonadotropin do not improve the outcomes, independently of maternal age. In addition, it has been thought that ovarian stimulation affects the natural selection of dominant follicles, increasing the failures in the division of oocytes and genomic imprinting [33]. Also, ovary stimulation during IVF treatment may influence oocyte maturation and the completion of meiosis, potentially mediating chromosomal aneuploidy and mosaicism [34]. Many studies have evaluate the factors influencing embryo aneuploidy [35–38]. Nevertheless, the mechanisms leading to aneuploidy are complex and not fully understood, especially on a cellular level [9, 26]. It is well known that embryonic aneuploidy is the primary cause of poor oocyte quality, embryo development arrest, implantation failure, early miscarriage, and overall reproductive failure [8, 39, 40]. Generation of a chromosomally competent embryo is dependent upon successful completion of meiosis in the oocyte, followed by fertilization to create an embryo with 23 unique pairs of chromosomes. This is an inefficient process in humans, with errors of meiosis resulting in chromosomal alterations [18]. Reproductive aging in the female is associated with a progressive increase in embryonic aneuploidy, due to meiotic and mitotic errors [41]. Several studies have investigated whether ovarian stimulations increase aneuploidy rate in women undergoing IVF. In 2010, twenty-two women were subject first to a standard dose gonadotropin protocol and then a lower dose protocol. The lower dose protocol resulted in fewer embryos, but higher rates of fertilization and euploid embryos [42]. More recently, Barash et al. [9] evaluated 4,034 embryos from women treated with low, medium, or high-dose gonadotropin protocols and did not identify differences in euploidy or pregnancy rates. Hong and co-workers [41] compared traditional ovarian stimulation IVF cycles to natural IVF cycles with only ovulation trigger medications utilized. They observed that ovarian stimulation with exogenous gonadotropin administration does not impact embryonic aneuploidy rates in humans. Sachdeva et al. [10] showed higher aneuploidy rate in women undergoing stimulation with higher gonadotropin dosages, similar to our results. This finding may reflect an increased tendency towards oocyte and embryonic aneuploidy in patients with a diminished response to gonadotropin stimulation. When comparing the kind of gonadotropin used in controlled ovarian stimulation, our results showed that IVF outcomes, such as number of follicles, retrieved oocytes, MII oocytes, zygotes, blastocysts and euploidy were higher for women of rFSH-only gonadotropin protocol. Although patients with rFSH-only protocol were younger than other protocols groups. For Mccullohe et al [43], hMG protocol had a trend to support euploidy. Our findings revealed that the use of hMG-only or combined to rFSH hade the worst outcomes. Nevertheless, similar to our results, another study had a trend in favor of FSH-only stimulation regarding euploidy rates and number of euploidy embryos [44]. Regarding infertility factors, maternal age was not significantly. The presence of a female plus male factor or female-only factor was the worst scenario for IVF oucomes and for embryo euploidy, followed by male factor only and the unexplained infertility factor showed the best euploidy. Similar to our results, Kort et al [45] presented that patients with unexplained and male factor infertility did not have a significantly different aneuploidy rate than fertile controls. Our results showed that lower doses of gonadotropin are more likely to produce more follicles, oocytes, mature oocytes, zygotes, more embryos and more euploid blastocysts when comparing to higher dose group. It was also observed a positive correlation between embryo production and euploidy. However, it was also found that the higher the dose of gonadotropin, the lower the IVF outcomes. It has been suggested that the low ovarian reserve and, consequently, the absence of follicles adequate for selection (non-viable) allows the selection for ovulation of these follicles, which are more likely to release an aneuploid oocyte. [46–50] Taking all together it is possible that lower gonadotropin dose has less impact on meiosis resumption and on chromosomes segregation. Thus, we can conclude that for women with average age 37–38 years old that are submitted to IVF treatment the higher euploid embryo rate is found using lower gonadotropin dose. Declarations Competing Interests: All authors declare they have no financial interests. The authors have no relevant financial or non-financial interests to disclose.” Ethics approval: This is an observational study. The PUC-Curitiba Research Ethics Committee has confirmed that no ethical approval is required. Consent to participate: Informed consent was obtained from all individual participants included in the study. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contributions: Alessandro Schuffner: Protocol/Projetc Development; Data analysis; Manuscript Writing/Editing Gabriela Schuffner: Data Collection or Management; Data analysis Camila Dutra De Souza Francisquini: Data Collection or Management Matheus Campos Carneiro: Data Collection Or Management Isadora Ferreira Kozlowski: Data Collection Or Management Samara Artuso Giacomin: Data Collection Or Management Vinicius Bonato Da Rosa: Protocol/Projetc Development; Data Analysis; Manuscript Writing/Editing Acknowledgements: The authors would like to thank all individuals and organizations that contributed to this study. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Data availability statement: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data are not available. However, anonymized data may be made available upon reasonable request to researchers who meet the criteria for access to confidential data. Requests should be directed to [email protected] References Leridon H. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Hum Reprod. 2004;19(7):1548-53. Kosteria I, Anagnostopoulos AK, Kanaka-Gantenbein C, Chrousos GP, Tsangaris GT. The Use of Proteomics in Assisted Reproduction. In Vivo. 2017;31(3):267 − 83. Lee ST, Kim TM, Cho MY, Moon SY, Han JY, Lim JM. Development of a hamster superovulation program and adverse effects of gonadotropins on microfilament formation during oocyte development. Fertil Steril. 2005;83 Suppl 1:1264-74. Roberts R, Iatropoulou A, Ciantar D, Stark J, Becker DL, Franks S, et al. Follicle-stimulating hormone affects metaphase I chromosome alignment and increases aneuploidy in mouse oocytes matured in vitro. Biol Reprod. 2005;72(1):107 − 18. Van der Auwera I, D'Hooghe T. Superovulation of female mice delays embryonic and fetal development. Hum Reprod. 2001;16(6):1237-43. Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22(4):980-8. Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, et al. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online. 2012;24(6):614 − 20. Sekhon L, Shaia K, Santistevan A, Cohn KH, Lee JA, Beim PY, et al. The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response. J Assist Reprod Genet. 2017;34(6):749 − 58. Barash OO, Hinckley MD, Rosenbluth EM, Ivani KA, Weckstein LN. High gonadotropin dosage does not affect euploidy and pregnancy rates in IVF PGS cycles with single embryo transfer. Hum Reprod. 2017;32(11):2209-17. Sachdeva K, Upadhyay D, Discutido R, Varghese MM, Albuz F, Almekosh R, et al. Low Gonadotropin Dosage Reduces Aneuploidy in Human Preimplantation Embryos: First Clinical Study in a UAE Population. Genet Test Mol Biomarkers. 2018;22(10):630-4. Munne S, Alikani M, Ribustello L, Colls P, Martinez-Ortiz PA, McCulloh DH, et al. Euploidy rates in donor egg cycles significantly differ between fertility centers. Hum Reprod. 2017;32(4):743-9. Irani M, Canon C, Robles A, Maddy B, Gunnala V, Qin X, et al. No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies. Hum Reprod. 2020;35(5):1082-9. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;340(8810):17 − 8. Gardner DK, Schoolcraft WB. Culture and transfer of human blastocysts. Curr Opin Obstet Gynecol. 1999;11(3):307 − 11. Alfarawati S, Fragouli E, Colls P, Stevens J, Gutierrez-Mateo C, Schoolcraft WB, et al. The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender. Fertil Steril. 2011;95(2):520-4. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. Hum Reprod Update. 2002;8(4):333 − 43. Munne S, Alikani M, Tomkin G, Grifo J, Cohen J. Reprint of: Embryo morphology, developmental rates, and maternal age are correlated with chromosome abnormalities. Fertil Steril. 2019;112(4 Suppl1):e71-e80. Thorne J, Loza A, Kaye L, Nulsen J, Benadiva C, Grow D, et al. Euploidy rates between cycles triggered with gonadotropin-releasing hormone agonist and human chorionic gonadotropin. Fertil Steril. 2019;112(2):258 − 65. Liu K, Case A, Reproductive E, Infertility C. Advanced reproductive age and fertility. J Obstet Gynaecol Can. 2011;33(11):1165-75. La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014;20(1):124 − 40. Siddiqui QUA, Anjum S, Zahra F, Yousuf SM. Ovarian reserve parameters and response to controlled ovarian stimulation in infertile patients. Pak J Med Sci. 2019;35(4):958 − 62. Howie R, Kay V. Controlled ovarian stimulation for in-vitro fertilization. Br J Hosp Med (Lond). 2018;79(4):194-9. Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M, et al. Anti-Mullerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009;24(4):867 − 75. Nyboe Andersen A, Nelson SM, Fauser BC, Garcia-Velasco JA, Klein BM, Arce JC, et al. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril. 2017;107(2):387 − 96 e4. Wang JG, Douglas NC, Dicken C, Nakhuda GS, Guarnaccia MM, Sauer MV. Cryopreservation of supernumerary high quality embryos predicts favorable outcomes for patients undergoing repeated cycles of in vitro fertilization. Fertil Steril. 2008;89(2):368 − 74. Wu Q, Li H, Zhu Y, Jiang W, Lu J, Wei D, et al. Dosage of exogenous gonadotropins is not associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women. Hum Reprod. 2018;33(10):1875-82. Kuliev A, Verlinsky Y. Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis. Hum Reprod Update. 2004;10(5):401-7. Vanneste E, Voet T, Melotte C, Debrock S, Sermon K, Staessen C, et al. What next for preimplantation genetic screening? High mitotic chromosome instability rate provides the biological basis for the low success rate. Hum Reprod. 2009;24(11):2679-82. Spielmann H, Vogel R. Genotoxic and embryotoxic effects of gonadotropin hyperstimulated ovulation on murine oocytes, preimplantation embryos and term fetuses. Ann Ist Super Sanita. 1993;29(1):35 − 9. Valbuena D, Martin J, de Pablo JL, Remohi´ J, Pellicer A, Simón C. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertility and Sterility. 2001;76(5):962-8. Lensen SF, Wilkinson J, Leijdekkers JA, La Marca A, Mol BWJ, Marjoribanks J, et al. Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). Cochrane Database Syst Rev. 2018;2:CD012693. Vaiarelli A, Cimadomo D, Ubaldi N, Rienzi L, Ubaldi FM. What is new in the management of poor ovarian response in IVF? Curr Opin Obstet Gynecol. 2018;30(3):155 − 62. Sato A, Otsu E, Negishi H, Utsunomiya T, Arima T. Aberrant DNA methylation of imprinted loci in superovulated oocytes. Hum Reprod. 2007;22(1):26–35. Check JH. Mild ovarian stimulation. J Assist Reprod Genet. 2007;24(12):621-7. Braga DP, Setti AS, Figueira Rde C, Iaconelli A, Jr., Borges E, Jr. Contributing factors for the incidence of aneuploidy in older patients undergoing intracytoplasmic sperm injection cycles. J Assist Reprod Genet. 2012;29(9):911-6. Demko ZP, Simon AL, McCoy RC, Petrov DA, Rabinowitz M. Effects of maternal age on euploidy rates in a large cohort of embryos analyzed with 24-chromosome single-nucleotide polymorphism-based preimplantation genetic screening. Fertil Steril. 2016;105(5):1307-13. Gat I, Tang K, Quach K, Kuznyetsov V, Antes R, Filice M, et al. Sperm DNA fragmentation index does not correlate with blastocyst aneuploidy or morphological grading. PLoS One. 2017;12(6):e0179002. Goldman KN, Hodes-Wertz B, McCulloh DH, Flom JD, Grifo JA. Association of body mass index with embryonic aneuploidy. Fertil Steril. 2015;103(3):744-8. Boue A, Boue J, Gropp A. Cytogenetics of pregnancy wastage. Adv Hum Genet. 1985;14:1–57. Hassold TJ, Jacobs PA. Trisomy in man. Annu Rev Genet. 1984;18:69–97. Hong KH, Franasiak JM, Werner MM, Patounakis G, Juneau CR, Forman EJ, et al. Embryonic aneuploidy rates are equivalent in natural cycles and gonadotropin-stimulated cycles. Fertil Steril. 2019;112(4):670-6. Rubio C, Mercader A, Alama P, Lizan C, Rodrigo L, Labarta E, et al. Prospective cohort study in high responder oocyte donors using two hormonal stimulation protocols: impact on embryo aneuploidy and development. Hum Reprod. 2010;25(9):2290-7. McCulloh DH, Alikani M, Norian J, Kolb B, Arbones JM, Munne S. Controlled ovarian hyperstimulation (COH) parameters associated with euploidy rates in donor oocytes. Eur J Med Genet. 2019;62(8):103707. Weghofer A, Munne S, Brannath W, Chen S, Barad D, Cohen J, et al. The impact of LH-containing gonadotropin stimulation on euploidy rates in preimplantation embryos: antagonist cycles. Fertil Steril. 2009;92(3):937 − 42. Kort JD, McCoy RC, Demko Z, Lathi RB. Are blastocyst aneuploidy rates different between fertile and infertile populations? J Assist Reprod Genet. 2018;35(3):403-8. Grande M, Borobio V, Bennasar M, Stergiotou I, Mercade I, Masoller N, et al. Role of ovarian reserve markers, antimullerian hormone and antral follicle count, as aneuploidy markers in ongoing pregnancies and miscarriages. Fertil Steril. 2015;103(5):1221-7 e2. Haadsma ML, Mooij TM, Groen H, Burger CW, Lambalk CB, Broekmans FJ, et al. A reduced size of the ovarian follicle pool is associated with an increased risk of a trisomic pregnancy in IVF-treated women. Hum Reprod. 2010;25(2):552-8. Pankhurst MW. A putative role for anti-Mullerian hormone (AMH) in optimising ovarian reserve expenditure. J Endocrinol. 2017;233(1):R1-R13. Rosen MP, Johnstone E, Addauan-Andersen C, Cedars MI. A lower antral follicle count is associated with infertility. Fertil Steril. 2011;95(6):1950-4, 4 e1. Warburton D. The effect of maternal age on the frequency of trisomy: change in meiosis or in utero selection? Prog Clin Biol Res. 1989;311:165 − 81. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4797800","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":340266796,"identity":"320df12d-0d67-40c3-a7b6-fa440d9a93e9","order_by":0,"name":"Alessandro Schuffner","email":"data:image/png;base64,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","orcid":"","institution":"Clinica Conceber","correspondingAuthor":true,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Schuffner","suffix":""},{"id":340266797,"identity":"cd63f0d4-9152-4e94-a6fc-b86e2ac2f592","order_by":1,"name":"Gabriela Schuffner","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"","lastName":"Schuffner","suffix":""},{"id":340266798,"identity":"b299fd80-72f6-4ffb-8bc2-d4eb59d90274","order_by":2,"name":"Camila Dutra De Souza Francisquini","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Camila","middleName":"Dutra De Souza","lastName":"Francisquini","suffix":""},{"id":340266799,"identity":"cfc5ab89-ea4d-4133-a25c-0e739e880d80","order_by":3,"name":"Matheus Campos Carneiro","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Matheus","middleName":"Campos","lastName":"Carneiro","suffix":""},{"id":340266800,"identity":"0e3636b3-c300-4638-88c6-f189beba9546","order_by":4,"name":"Isadora Ferreira Kozlowski","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Isadora","middleName":"Ferreira","lastName":"Kozlowski","suffix":""},{"id":340266801,"identity":"af4ed35a-19fc-47da-ab81-92458fae12de","order_by":5,"name":"Samara Artuso Giacomin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Samara","middleName":"Artuso","lastName":"Giacomin","suffix":""},{"id":340266802,"identity":"91195c8d-6ddf-47ec-86d9-5de396c95286","order_by":6,"name":"Vinicius Bonato Da Rosa","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Vinicius","middleName":"Bonato Da","lastName":"Rosa","suffix":""}],"badges":[],"createdAt":"2024-07-24 21:22:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4797800/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4797800/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66464586,"identity":"2a4025a1-e011-4d6f-ada3-a327906fd643","added_by":"auto","created_at":"2024-10-12 12:48:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":712366,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4797800/v1/64ab9d8b-fa89-4d60-9f60-4fdda7b08e0d.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eImpact of Gonadotrophin Dose Used on Ovarian Stimulation for IVF on Embryo Ploidy Status\u003c/p\u003e","fulltext":[{"header":"What does this study adds to the clinical work","content":"\u003cp\u003eLower doses of gonadotropin are more likely to produce more embryos and more euploid blastocysts and the higher the dose of gonadotropin, the lower the production of euploid embryos.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eAssisted reproductive technologies (ART) is often the primary choice to treat human infertility. However, ART cannot fully compensate for female age-dependent loss of oocyte quality and quantity due to the fact that the success rates of these techniques also decrease with age [1]. In addition, hormonal hyperstimulation protocols, which include the use of gonadotropin to induce multiple ovulations are known to create a hostile endometrial environment [2].\u003c/p\u003e \u003cp\u003eIn animal models studies it was observed that superovulation accelerate nuclear maturation and affect chromosome during prometaphase and metaphase, thus causing a higher risk of aneuploidies [3\u0026ndash;5].\u003c/p\u003e \u003cp\u003eResearchers have investigated whether ovary hyperstimulation increases aneuploidy rate in women undergoing ART. It was suggested that stimulation with high-dose exogenous gonadotropins (225 IU recombinant FSH; rec-FSH) might lead to higher aneuploidy rates compared to mild (150 IU rec-FSH) stimulation [6]. A study published in 2012 showed no association between the number of embryos generated and aneuploidy rates [7]. Sekhon et al. [8] reported that exogenous gonadotropins did not significantly modify the aneuploidy rates in cases with up to 12 days of ovarian stimulation. In the same year, Barash and coworkers [9] showed that euploidy rates within the same age group were not statistically different regardless of the total dosage of gonadotropins (\u0026gt;\u0026thinsp;5000 IU or \u0026lt;\u0026thinsp;3000 IU). A retrospective study also showed higher aneuploidy rates in women undergoing stimulation with higher gonadotropin (\u0026ge;\u0026thinsp;200 IU) dosages [10]. Moreover, Munn\u0026eacute; et al. [11] demonstrated a significant difference in euploidy rates, ranging from 39.5 to 82.5%, among young oocyte donors. Therefore, determining the effect of exogenous gonadotropins on embryo ploidy in women undergoing ovarian stimulation is critical for the selection of the best stimulation protocols [12].\u003c/p\u003e \u003cp\u003eStudies exploring the relationship ovarian stimulation using gonadotropin and embryo euploidy have yielded inconclusive results, and some degree of controversy remains. Given the conflicting reports and lack of guidance regarding gonadotropin dosing, our goal was to evaluate de total amount of gonadotropin used during an IVF cycle and the number of euploid embryos produced after blastomere biopsy by patients of different ages.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eExperimental design and localization\u003c/h2\u003e \u003cp\u003eAn observational, descriptive, and retrospective study was performed between February 2012 and December 2019 in an IVF Clinic at Curitiba, Paran\u0026aacute;, Brazil.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThe electronic registration of 1500 women that underwent IFV treatment with ovarian stimulations and preimplantation genetic testing for aneuploidies (PGT-A) between February 2012 and December 2019 were analyzed. Exclusion criteria were patients with low ovarian reserve, ovarian surgery, use of surgically retrieved semen for IVF, use of GnRH agonist for pituitary suppression and absence of PGT-A result.\u003c/p\u003e \u003cp\u003eAfter exclusion criteria, the remaining 245 patients were divided in two experimental groups considering the total gonadotropin dose used during IVF treatment (Group\u0026thinsp;\u0026le;\u0026thinsp;3000 IU n\u0026thinsp;=\u0026thinsp;150; or Group\u0026thinsp;\u0026gt;\u0026thinsp;3000 IU n\u0026thinsp;=\u0026thinsp;95). After, for more statistical analysis, they were divided in five groups according kind of gonadotropin protocol (hMG-only n\u0026thinsp;=\u0026thinsp;66; rFSH-only n\u0026thinsp;=\u0026thinsp;90; rFSH\u0026thinsp;+\u0026thinsp;hMG n\u0026thinsp;=\u0026thinsp;58; rFSH\u0026thinsp;+\u0026thinsp;rLH n\u0026thinsp;=\u0026thinsp;22 or uFSH n\u0026thinsp;=\u0026thinsp;9). Moreover, patients were divided in four groups considering infertility diagnosis (female n\u0026thinsp;=\u0026thinsp;163; male and female n\u0026thinsp;=\u0026thinsp;23; male n\u0026thinsp;=\u0026thinsp;28 or Unexplained n\u0026thinsp;=\u0026thinsp;31).\u003c/p\u003e \u003cp\u003eThe following data were collected: maternal age, infertility factors, gonadotropin dosage, the average ovarian stimulation period, the kind of gonadotropin, number of follicles, oocytes retrieved and metaphase II (MII), zygotes, blastocysts, number and rate of euploid embryos.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOvarian stimulation protocols\u003c/h2\u003e \u003cp\u003eAll patients underwent controlled ovarian stimulation protocols according to the patient\u0026acute;s baseline characteristics and previous medical history. GnRH antagonist was used for pituitary suppression. Recombinant follicle stimulating hormone (rFSH) alone or in combination with human menopausal gonadotropin (hMG) or recombinant luteinizing hormone (rLH), hMG alone or urinary FSH (uFSH) alone were used as options of exogenous gonadotropin. Human chorionic gonadotropin (hCG) was used for triggering ovulation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOocyte retrieval\u003c/h2\u003e \u003cp\u003eApproximately 35 hours after the hCG injection, the oocyte retrieval was performed under sedation. After retrieval, oocytes were incubated in culture medium CSCM-C (Irvine Scientific\u0026reg; Santa Ana, USA) covered with mineral oil (Oil for Embryo Culture, Irvine Scientific\u0026reg; Santa Ana, USA) at 37\u0026ordm;C and 6% CO\u003csub\u003e2\u003c/sub\u003e for 4 hours.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eIntracitoplasmic sperm injection (ICSI)\u003c/h2\u003e \u003cp\u003eICSI was performed according to Palermo et al [13]. For ICSI, oocytes were placed individually in 3 \u0026micro;L droplets of buffered medium HTF (Irvine Scientific\u0026reg;, Santa Ana, USA). Sperm were placed in a central 5 \u0026micro;L droplet of polyvinylpyrrolidone solution (PVP, Irvine Scientific, Santa Ana, USA) in a 50X9 mm glass culture dish covered with warm mineral oil (Oil for Embryo Culture, Irvine Scientific\u0026reg; Santa Ana, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of fertilization and embryo quality\u003c/h2\u003e \u003cp\u003eEmbryos were placed in a 50-\u0026micro;L drop of culture medium CSCM-C (Irvine Scientific\u0026reg; Santa Ana, USA) supplemented with 10% protein supplement, and were covered with paraffin oil in a humidified atmosphere under 7.5% CO\u003csub\u003e2\u003c/sub\u003e at 37\u0026ordm;C for 5 days. Fertilization was assessed 18 hours after ICSI, and normal fertilization (zygote) was declared when two clearly distinct pronuclei were present. Blastocyst quality was evaluated under an inverted microscope [14].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBiopsy and embryo cryopreservation\u003c/h2\u003e \u003cp\u003eFor blastocyst biopsy, the embryos underwent assisted hatching with zona pellucida laser pulsing (OCTAX Laser Shot\u0026trade;; MTG Medical Technology, Germany) on day 3 of development. Only good-quality blastocysts were biopsied on day 5, in a 20-\u0026micro;L drop of buffered medium with 10% protein supplement and covered with paraffin oil. The hatching of the zona pellucida and trophectoderm was disposed at the 3 o\u0026rsquo;clock position, and gentle suction was applied to the blastocyst via a holding pipette (Humagen, Charlottesville, VA). A biopsy pipette (Humagen, Charlottesville, VA) was used to gently aspirate the trophectoderm into the bore of the needle. Laser pulses were used to \"cut\" the trophectoderm.\u003c/p\u003e \u003cp\u003eAfter biopsy, embryos were vitrified. Both vitrification and the warming procedures were performed using the Frozen/Thawing Kit (Ingamed\u0026reg;, Londrina, Brazil).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEmbryo diagnosis\u003c/h2\u003e \u003cp\u003eThe diagnosis was performed by NGS in an associated genetic laboratory, according to its established methodology.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eNormal distribution was evaluated by Shapiro-Wilk test. Since all dependent variables did not show normal distribution, the Kruskal-Wallis and Dunn\u0026acute;s post hoc non-parametric tests were used. Spearman rank correlation coefficient was used for the correlation test. Data were evaluated using the MedCalc Software, version 20.006. A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThere was no interaction between the independent variables (gonadotropin dosage, kind of gonadotropin and infertility diagnosis) for all measured dependent variables, so their effects were tested individually.\u003c/p\u003e \u003cp\u003eWhen evaluating both groups regarding gonadotropin dosage (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) it was observed that the average maternal age was not different between the groups (p\u0026thinsp;=\u0026thinsp;0.47). The median age of group\u0026thinsp;\u0026le;\u0026thinsp;3000 IU was 37.54 (\u0026plusmn;\u0026thinsp;4.16) years old, while in the group\u0026thinsp;\u0026gt;\u0026thinsp;3000 IU was 38.08 (\u0026plusmn;\u0026thinsp;3.57) years old.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; \u003cem\u003eIn vitro\u003c/em\u003e fertilization outcomes (ovarian stimulation period. number of follicles. number of oocytes and mature oocytes retrieved (MII). number of zygotes. blastocysts produced. number and rate of euploid embryos) and maternal age (years) according to gonadotropin dosage group (IU). Data presented as Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGonadotropin Dosage Groups (n)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;3000 IU (150)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3000 IU (95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.54\u0026thinsp;\u0026plusmn;\u0026thinsp;4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvarian stimulation period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.46\u0026thinsp;\u0026plusmn;\u0026thinsp;1.72\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.80\u0026thinsp;\u0026plusmn;\u0026thinsp;2.07\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of follicles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.68\u0026thinsp;\u0026plusmn;\u0026thinsp;7.18\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.48\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOocytes retrieved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.81\u0026thinsp;\u0026plusmn;\u0026thinsp;7.06\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.15\u0026thinsp;\u0026plusmn;\u0026thinsp;5.80\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMII oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.43\u0026thinsp;\u0026plusmn;\u0026thinsp;5.34\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.71\u0026thinsp;\u0026plusmn;\u0026thinsp;4.75\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZygotes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.15\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.27\u0026thinsp;\u0026plusmn;\u0026thinsp;3.14\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlastocyst\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.26\u0026thinsp;\u0026plusmn;\u0026thinsp;2.40\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.29\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.82\u0026thinsp;\u0026plusmn;\u0026thinsp;33.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.17\u0026thinsp;\u0026plusmn;\u0026thinsp;38.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eDifferent superscript letters in each line represent significant differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHowever, patients from group\u0026thinsp;\u0026le;\u0026thinsp;3000 IU had a shorter ovarian stimulation period when compared to women that received\u0026thinsp;\u0026gt;\u0026thinsp;3000 IU gonadotropin (P\u0026thinsp;\u0026lt;\u0026thinsp;0.000001). Despite shorter stimulation period, patients from group\u0026thinsp;\u0026le;\u0026thinsp;3000 IU produced higher number of follicles (p\u0026thinsp;=\u0026thinsp;0.001963), oocytes retrieved (p\u0026thinsp;=\u0026thinsp;0.000698), MII retrieved (p\u0026thinsp;=\u0026thinsp;0.006211), zygotes (p\u0026thinsp;=\u0026thinsp;0.000416), number of blastocysts (p\u0026thinsp;=\u0026thinsp;0.000019) and euploid blastocysts (p\u0026thinsp;=\u0026thinsp;0.03). On the other hand, the groups were equal regarding euploid embryo rate.\u003c/p\u003e \u003cp\u003eWhen evaluating the kind of gonadotropin protocol, the sample was divided in five groups (hMG-only, rFSH-only, hMG plus rFSH, rFSH plus rLH or uFSH). (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The average maternal age was lower in the rFSH-only group and uFSH group than hMG plus rFSH group (p\u0026thinsp;=\u0026thinsp;0.004607).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; \u003cem\u003eIn vitro\u003c/em\u003e fertilization outcomes (ovarian stimulation period. number of follicles. number of oocytes and mature oocytes retrieved (MII). number of zygotes. blastocysts produced. number and rate of euploid embryos) and maternal age (years) according to kind of gonadotropin protocol. Data presented as Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eKind of gonadotropin protocol (n)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehMG-only (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003erFSH-only (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003erFSH\u0026thinsp;+\u0026thinsp;hMG (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003erFSH\u0026thinsp;+\u0026thinsp;rLH (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003euFSH\u003c/p\u003e \u003cp\u003e(9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.33 \u003csup\u003eab\u003c/sup\u003e \u0026plusmn; 3.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.61\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.84\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.45\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.22\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvarian stimulation period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.34\u0026thinsp;\u0026plusmn;\u0026thinsp;2.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.23\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.69\u0026thinsp;\u0026plusmn;\u0026thinsp;2.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.72\u0026thinsp;\u0026plusmn;\u0026thinsp;2.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of follicles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.39\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;5.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.52\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;7.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.26\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.18\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.00\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOocytes retrieved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.65\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;5.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.55\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;7.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.53\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.54\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;8.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.89\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;5.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMII oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.03\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.22\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;5.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.89\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.27\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.78\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;5.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZygotes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.72\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.98\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.07\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.86\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;2.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.89\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlastocyst\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.37\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.76\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.14\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.47\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.55\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.75\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.38\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.65\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.90\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.89\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.31\u0026thinsp;\u0026plusmn;\u0026thinsp;31.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.42\u0026thinsp;\u0026plusmn;\u0026thinsp;31.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.68\u0026thinsp;\u0026plusmn;\u0026thinsp;39.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.24\u0026thinsp;\u0026plusmn;\u0026thinsp;46.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.11\u0026thinsp;\u0026plusmn;\u0026thinsp;35.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eDifferent superscript letters in each line represent significant differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegardless of the kind of gonadotropin used, the average ovarian stimulation period was statistically similar. The number of follicles was greater in the group rFSH-only when compared with the number of follicles produced by patients with other gonadotropin protocols (p\u0026thinsp;=\u0026thinsp;0.000002). Also, the number of retrieved oocytes (p\u0026thinsp;=\u0026thinsp;0.000012), MII oocytes (p\u0026thinsp;=\u0026thinsp;0.000001) and zygotes (p\u0026thinsp;=\u0026thinsp;0.000001) were higher for women of rFSH-only gonadotropin protocol compared to other four gonadotropin protocol. Number of blastocysts (p\u0026thinsp;=\u0026thinsp;0.000147) and euploid embryos (p\u0026thinsp;=\u0026thinsp;0.003974) were greater in the rFSH-only group than hMG-only and hMG plus rFSH group. On the other hand, the groups were equal regarding euploid embryo rate.\u003c/p\u003e \u003cp\u003eThe infertility diagnosis was also evaluated, and the sample was divided in four groups according the diagnosis as female, female plus male, male and unexplained (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The maternal age and ovarian stimulation period were similar among the groups. The number of follicles (p\u0026thinsp;=\u0026thinsp;0.000035), oocytes retrieved (p\u0026thinsp;=\u0026thinsp;0.000052), MII oocytes (p\u0026thinsp;=\u0026thinsp;0.002277) and zygotes (p\u0026thinsp;=\u0026thinsp;0.006993) were greater in the male factor group and unexplained factor compared to female plus male and mainly with female factor group. Independently of the infertility factor, number of blastocysts was similar among the groups. However, the number of euploid blastocysts was greater in the unexplained factor group (p\u0026thinsp;=\u0026thinsp;0.020338), and the female plus male group showed the lowest euploidy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; \u003cem\u003eIn vitro\u003c/em\u003e fertilization outcomes (ovarian stimulation period. number of follicles. number of oocytes and mature oocytes retrieved (MII). number of zygotes. blastocysts produced. number and rate of euploid embryos) and maternal age (years) according to infertility diagnosis. Data presented as Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003cp\u003e(163)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale and female (23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003e(28)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnexplained (31)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.01\u0026thinsp;\u0026plusmn;\u0026thinsp;3.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.65\u0026thinsp;\u0026plusmn;\u0026thinsp;5.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.35\u0026thinsp;\u0026plusmn;\u0026thinsp;4.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.48\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvarian stimulation period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.49\u0026thinsp;\u0026plusmn;\u0026thinsp;2.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.06\u0026thinsp;\u0026plusmn;\u0026thinsp;2.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of follicles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.64\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;6.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.65\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.96\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;7.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.45\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;7.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOocytes retrieved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.81\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;6.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.13\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.39\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;7.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.19\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;6.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMII oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.27\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;5.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.17\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.85\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.90\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZygotes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.00\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.52\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.93\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.19\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;3.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlastocyst\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.65\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.39\u0026thinsp;\u0026plusmn;\u0026thinsp;2.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.92\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.56\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.21\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.38\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;1.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.85\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;36.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.72\u003csup\u003ea\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;26.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.96\u003csup\u003eb\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;33.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37.68\u003csup\u003eab\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;32.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eDifferent superscript letters in each line represent significant differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe correlation rate among maternal age, gonadotropin dosage, ovarian stimulation period, number of follicles, retrieved oocytes, MII occytes, zygotes, blastocyst production and euploid embryos is shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; Correlations (r) and significance levels (P) among the measured variables.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMaternal age (y)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOvarian stimulation period\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGonadotropin Dosage (IU)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNumber of follicles\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOocytes retrieved\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMII oocytes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eZygotes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBlastocyst\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eEuploid embryo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eEuploid embryo rate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.095\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.1369)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.3352)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.418\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.387\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.381\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.342\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.367\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-0.430\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-0.357\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvarian stimulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.095\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.1369)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.5119)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.006\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.9285)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.7689)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.018\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.7754)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.019\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.7619)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.6414)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.5302)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGonadotropin Dosage (IU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.3352)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.169\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0079)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.200\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.163\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0106)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.195\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.236\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-0.133\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0379)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-0.043\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.5063)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of follicles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.418\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.5119)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.169\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0079)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.942\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.904\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.819\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.442\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.214\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0007)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOocytes retrieved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.387\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.006\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.9285)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.200\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.942\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.935\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.842\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.632\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.205\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0013)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMII oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.381\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.7689)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.163\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0106)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.904\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.935\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.872\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.642\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.458\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0011)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZygotes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.342\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.018\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.7754)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.195\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.819\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.842\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.872\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.726\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.228\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0003)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlastocyst\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.367\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.019\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.7619)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.236\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.632\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.642\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.726\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.624\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.277\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.430\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.6414)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.133\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0379)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.442\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.458\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.624\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.864\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuploid embryo rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.357\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.5302)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.043\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.5063)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.214\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0007)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.205\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0013)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.228\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;=\u0026thinsp;0.0003)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.277\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.864\u003c/p\u003e \u003cp\u003e(p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA negative correlation was found between maternal age and number of follicles, oocytes retrieved, MII retrieved, zygotes, blastocysts and euploid blastocysts (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Maternal age did not correlated with gonadotropin dosage (p\u0026thinsp;=\u0026thinsp;0.3352) or ovarian stimulation period (p\u0026thinsp;=\u0026thinsp;0.1369).\u003c/p\u003e \u003cp\u003eAs expected, there was a positive correlation between period of ovary stimulation and total gonadotropin dose (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). However, the gonadotropin dose is negatively correlated to number of follicles (p\u0026thinsp;=\u0026thinsp;0.0079), oocytes retrieved (p\u0026thinsp;=\u0026thinsp;0.0017), MII retrieved (p\u0026thinsp;=\u0026thinsp;0.0106), zygotes (p\u0026thinsp;=\u0026thinsp;0.0022), blastocyst production (p\u0026thinsp;=\u0026thinsp;0.0002) and euploid embryos (p\u0026thinsp;=\u0026thinsp;0.0379).\u003c/p\u003e \u003cp\u003eEuploid embryos were negatively correlated to maternal age (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and gonadotropin dose (p\u0026thinsp;=\u0026thinsp;0.0379). Conversely, a positive correlation was found among euploidy and number of follicles, oocytes retrieved, MII retrieved, number of zygotes and blastocysts and euploidy rate (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eSeveral studies have revealed that over half of human preimplantation embryos produced by IVF treatment have chromosomal abnormalities [6, 15\u0026ndash;17]. There are several factors in the IVF process that may influence ploidy status, including maternal age, gonadotropin stimulation, oocyte trigger, embryo culture conditions and even iatrogenic origin [9, 11, 18]. Yet, ovarian stimulation of suboptimal follicles containing poorer quality oocytes that would have otherwise been naturally selected to undergo atresia, has been hypothesized to increase oocyte aneuploidy [8].\u003c/p\u003e \u003cp\u003eThe reported results here demonstrate that when comparing total gonadotropin doses or infertility factors, maternal age was not significant different. Although there was no significant difference in maternal age between the gonadotropin dosage groups, women with \u0026gt;\u0026thinsp;35 years of age usually experience a gradual loss of oocyte quality and quantity [12, 19]. Nevertheless, maternal age was positively related to the kind of gonadotropin used, since the oldest women were at hMG plus rFSH group, while the newest women were at rFSH-only group.\u003c/p\u003e \u003cp\u003eStill, we found a negative correlation between IVF outcomes (number of follicles, oocytes and mature oocytes retrieved, zygotes, embryo production and euploidy) and maternal age. According to Alfarawati and co-workers [15] there is a strong association between maternal age and aneuploidy, increasing from 51% in embryos of patients aged 31\u0026ndash;37 years to 60.7% in the embryos of women aged 38\u0026ndash;47 years. Therefore, even with the exclusion of low ovarian reserve in the sample, it is possible that some patients included in the present study had at least some degree of decreased ovarian reserve (also called poor responder patients). Ovarian reserve determines the capacity of the ovary to produce oocytes that are capable of fertilization. Age is an important factor for ovarian reserve quality and quantity determination [20, 21] .\u003c/p\u003e \u003cp\u003eThe main goal of controlled ovarian stimulation with exogenous gonadotropins is to maximize the number of oocytes retrieved. Traditionally GnRH agonists have been used as a long protocol of ovarian stimulation [8, 22]. On the other hand, GnRH antagonists which prevent a premature LH surge were introduced as an alternative to the GnRH agonists allowing a shorter duration of treatment. The longer regimen of ovarian stimulation is associated with higher gonadotrophin consumption than shorter protocols. Yet, since the GnRH antagonist regimen (shorter protocol) avoids severe suppression of endogenous gonadotropins concentrations at the stage of follicular recruitment, this may be an advantage for older patients [20, 23]. All of the patients at this study underwent to GnRH antagonist protocol. Anyhow, the results showed here agree with published literature. The group that received lower dose of total gonadotropin (\u0026le;\u0026thinsp;3000 IU) showed shorter period of ovary stimulation when compared to patients that received higher gonadotropin doses.\u003c/p\u003e \u003cp\u003eReports on the effects of high versus low gonadotropin stimulation on IVF outcomes present conflicting data [24, 25]. A report published by Wu and co-workers [26] showed that women with advanced maternal age (\u0026ge;\u0026thinsp;35 years of age) had no difference in the rate of blastocyst aneuploidy among different gonadotropins dose groups (\u0026lt;\u0026thinsp;1500 IU, 58.0%; 1500\u0026ndash;3000 IU, 59.8%; and \u0026gt;\u0026thinsp;3000 IU, 59.8%; P\u0026thinsp;=\u0026thinsp;0.86). In contrast, some studies suggested that high gonadotropin doses might be associated with meiotic divisions errors [6, 17]. It could be speculated that high doses may be associated with the malfunction of intracellular reparation mechanisms and/or achromatic mitosis spindle assembly [27, 28]. Several studies have suggested that a high response to ovarian stimulation might be embryotoxic and/or increase oocyte aneuploidy rates by enhancing abnormal segregation of chromosomes during meiosis [3\u0026ndash;5, 29, 30]. Barash et al. [9] observed that the proportion of good quality embryos decreased from 48.92\u0026ndash;38.3%, while total dosage increased from under 3000 IU to over 5000 IU.\u003c/p\u003e \u003cp\u003eOur results support findings which reported that lower dose of gonadotropin showed increased embryo yield. It was also observed that gonadotropin dose is inversely correlated to all IVF outcomes, including number of euploidy, but not euploidy rate. The number of oocytes retrieved is associated with the dose of gonadotrophin, but this can vary between individual women [31]. However, higher doses of gonadotrophins cannot compensate for the absence of follicles in the ovary [32], therefore increased doses of gonadotrophins are likely to be cost-effective only when there is adequate ovarian reserve [22]. This study supports that high doses of gonadotropin do not improve the outcomes, independently of maternal age.\u003c/p\u003e \u003cp\u003eIn addition, it has been thought that ovarian stimulation affects the natural selection of dominant follicles, increasing the failures in the division of oocytes and genomic imprinting [33]. Also, ovary stimulation during IVF treatment may influence oocyte maturation and the completion of meiosis, potentially mediating chromosomal aneuploidy and mosaicism [34].\u003c/p\u003e \u003cp\u003eMany studies have evaluate the factors influencing embryo aneuploidy [35\u0026ndash;38]. Nevertheless, the mechanisms leading to aneuploidy are complex and not fully understood, especially on a cellular level [9, 26]. It is well known that embryonic aneuploidy is the primary cause of poor oocyte quality, embryo development arrest, implantation failure, early miscarriage, and overall reproductive failure [8, 39, 40]. Generation of a chromosomally competent embryo is dependent upon successful completion of meiosis in the oocyte, followed by fertilization to create an embryo with 23 unique pairs of chromosomes. This is an inefficient process in humans, with errors of meiosis resulting in chromosomal alterations [18]. Reproductive aging in the female is associated with a progressive increase in embryonic aneuploidy, due to meiotic and mitotic errors [41].\u003c/p\u003e \u003cp\u003eSeveral studies have investigated whether ovarian stimulations increase aneuploidy rate in women undergoing IVF. In 2010, twenty-two women were subject first to a standard dose gonadotropin protocol and then a lower dose protocol. The lower dose protocol resulted in fewer embryos, but higher rates of fertilization and euploid embryos [42]. More recently, Barash et al. [9] evaluated 4,034 embryos from women treated with low, medium, or high-dose gonadotropin protocols and did not identify differences in euploidy or pregnancy rates. Hong and co-workers [41] compared traditional ovarian stimulation IVF cycles to natural IVF cycles with only ovulation trigger medications utilized. They observed that ovarian stimulation with exogenous gonadotropin administration does not impact embryonic aneuploidy rates in humans. Sachdeva et al. [10] showed higher aneuploidy rate in women undergoing stimulation with higher gonadotropin dosages, similar to our results. This finding may reflect an increased tendency towards oocyte and embryonic aneuploidy in patients with a diminished response to gonadotropin stimulation.\u003c/p\u003e \u003cp\u003eWhen comparing the kind of gonadotropin used in controlled ovarian stimulation, our results showed that IVF outcomes, such as number of follicles, retrieved oocytes, MII oocytes, zygotes, blastocysts and euploidy were higher for women of rFSH-only gonadotropin protocol. Although patients with rFSH-only protocol were younger than other protocols groups. For Mccullohe \u003cem\u003eet al\u003c/em\u003e [43], hMG protocol had a trend to support euploidy. Our findings revealed that the use of hMG-only or combined to rFSH hade the worst outcomes. Nevertheless, similar to our results, another study had a trend in favor of FSH-only stimulation regarding euploidy rates and number of euploidy embryos [44].\u003c/p\u003e \u003cp\u003eRegarding infertility factors, maternal age was not significantly. The presence of a female plus male factor or female-only factor was the worst scenario for IVF oucomes and for embryo euploidy, followed by male factor only and the unexplained infertility factor showed the best euploidy. Similar to our results, Kort \u003cem\u003eet al\u003c/em\u003e [45] presented that patients with unexplained and male factor infertility did not have a significantly different aneuploidy rate than fertile controls.\u003c/p\u003e \u003cp\u003eOur results showed that lower doses of gonadotropin are more likely to produce more follicles, oocytes, mature oocytes, zygotes, more embryos and more euploid blastocysts when comparing to higher dose group. It was also observed a positive correlation between embryo production and euploidy. However, it was also found that the higher the dose of gonadotropin, the lower the IVF outcomes. It has been suggested that the low ovarian reserve and, consequently, the absence of follicles adequate for selection (non-viable) allows the selection for ovulation of these follicles, which are more likely to release an aneuploid oocyte. [46\u0026ndash;50] Taking all together it is possible that lower gonadotropin dose has less impact on meiosis resumption and on chromosomes segregation. Thus, we can conclude that for women with average age 37\u0026ndash;38 years old that are submitted to IVF treatment the higher euploid embryo rate is found using lower gonadotropin dose.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests:\u003c/h2\u003e \u003cp\u003eAll authors declare they have no financial interests. The authors have no relevant financial or non-financial interests to disclose.\u0026rdquo;\u003c/p\u003e \u003ch2\u003eEthics approval:\u003c/h2\u003e \u003cp\u003eThis is an observational study. The PUC-Curitiba Research Ethics Committee has confirmed that no ethical approval is required.\u003c/p\u003e \u003ch2\u003eConsent to participate:\u003c/strong\u003e \u003cp\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contributions:\u003c/h2\u003e\u003cp\u003eAlessandro Schuffner: Protocol/Projetc Development; Data analysis; Manuscript Writing/Editing\u003c/p\u003e\n\u003cp\u003eGabriela Schuffner:\u0026nbsp;Data Collection or Management; Data analysis\u003c/p\u003e\n\u003cp\u003eCamila Dutra De Souza Francisquini: Data Collection or Management\u003c/p\u003e\n\u003cp\u003eMatheus Campos Carneiro: Data Collection Or Management\u003c/p\u003e\n\u003cp\u003eIsadora Ferreira Kozlowski: Data Collection Or Management\u003c/p\u003e\n\u003cp\u003eSamara Artuso Giacomin: Data Collection Or Management\u003c/p\u003e\n\u003cp\u003eVinicius Bonato Da Rosa: Protocol/Projetc Development; Data Analysis; Manuscript Writing/Editing\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe authors would like to thank all individuals and organizations that contributed to this study. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eData availability statement:\u003c/h2\u003e \u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data are not available. However, anonymized data may be made available upon reasonable request to researchers who meet the criteria for access to confidential data. Requests should be directed to [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eLeridon H. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. 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A lower antral follicle count is associated with infertility. Fertil Steril. 2011;95(6):1950-4, 4 e1.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWarburton D. The effect of maternal age on the frequency of trisomy: change in meiosis or in utero selection? Prog Clin Biol Res. 1989;311:165\u0026thinsp;\u0026minus;\u0026thinsp;81.\u003c/span\u003e\u003c/li\u003e\n \n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ovulation induction, aneuploidy, in vitro fertilization, preimplantation embryo","lastPublishedDoi":"10.21203/rs.3.rs-4797800/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4797800/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eDoes the amount of gonadotrophin used during an IVF cycle affect the the number of euploid embryos by patients of different ages?\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA descriptive, retrospective, observational study with 245 patients divided in two experimental groups considering the total gonadotropin dose used (\u0026le;\u0026thinsp;3000 IU n\u0026thinsp;=\u0026thinsp;150 or \u0026gt;\u0026thinsp;3000 IU n\u0026thinsp;=\u0026thinsp;45).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePatients from group\u0026thinsp;\u0026le;\u0026thinsp;3000 IU had a shorter stimulation period, higher number of follicles, oocytes and MII retrieved, zygotes, number of blastocysts and euploid blastocysts. Regarding the kind of protocol, patients in rFSH-only group were younger, with more follicles, total and MII retrieved oocytes, zygotes, number of blastocysts and euploid blastocysts. When evaluating infertility diagnosis, the number of follicles, total and MII retrieved oocytes and zygotes were greater in the male factor group and unexplained factor compared to female plus male and mainly with female factor group. Moreover, the number of euploid blastocysts was greater in the unexplained factor group, and the female plus male group showed the lowest euploidy. A positive correlation was found between IVF outcomes and euploidy. A negative correlation was observed between embryo euploidy and maternal age and gonadotropin dose.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eLower doses of gonadotropin are more likely to produce more euploid blastocysts when comparing to higher dose group. The use of rFSH is related to younger patients and more euploid embryos. When female factor is present there was lower euploidy. It was also observed a positive correlation between embryo production and euploidy.\u003c/p\u003e","manuscriptTitle":"Impact of Gonadotrophin Dose Used on Ovarian Stimulation for IVF on Embryo Ploidy Status","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-11 07:27:38","doi":"10.21203/rs.3.rs-4797800/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"96c54e7a-7269-47f5-a1d8-93c2b4e9d717","owner":[],"postedDate":"September 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-12T12:40:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-11 07:27:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4797800","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4797800","identity":"rs-4797800","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}